Iodixanol is the non-proprietory name of the chemical drug substance of a non-ionic X-ray contrast agent marketed under the trade name Visipaque™. Visipaque™ is one of the most used agents in diagnostic X-ray procedures and is manufactured in large quantities.
The manufacture of such non-ionic X-ray contrast agents involves the production of the chemical drug substance (referred to as primary production) followed by formulation into the drug product (referred to as secondary production). Primary production of iodixanol involves a multi step chemical synthesis and a thorough purification process. For a commercial drug product it is important for the primary production to be efficient and economical and to provide a drug substance fulfilling the specifications, e.g. as expressed in the US Pharmacopea.
A number of methods are known for the preparation of iodixanol. These are all multi step chemical synthetic processes and the cost of the final formulated product thus mainly depends on these processes. It is therefore important to optimize the processes both for economic and environmental reasons.
In a preferred method for the preparation of iodixanol described in EP 108638, which document is hereby incorporated by reference, the final intermediate 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide (hereinafter “Compound A”) is reacted with a dimerisation agent such as epichlorohydrin to yield the drug substance, see Scheme I.

The reaction is usually carried out in the non-aqueous solvent 2-methoxyethanol and generally results in the conversion of 40 to 60% of Compound A to iodixanol. The product contains large amounts of impurities and is normally purified by crystallization. Too large amounts of impurities make the purification difficult and to achieve the desired purity, the crude iodixanol produced by the synthetic chemical process is crystallized twice. The process is time consuming and takes about 3 days for the first crystallization and about 2 days for the second one. Hence, the crystallization process is very demanding in terms of time and equipment size, it will take several days to perform and is often a bottleneck in industrial scale processes.
It is hence a desire to identify alternative low-cost and easily accessible solvents that can be used in the dimerisation step and that fulfill the above-mentioned criteria.
WO 99/18054 describes a method of crystallization of iodixanol where a solvent mixture comprising methanol and propan-2-ol is used in the example. A vast number of other general solvents are suggested, however many of these will not be feasible in an industrial scale and there are no suggestions regarding how to perform the crystallization in terms ratios or process parameters.
U.S. Pat. No. 5,349,085 describes a method of preparing iodixanol wherein water is used as solvent at room temperature with epichlorohydrin as dimerisation agent.
WO 98/23296 teaches the synthesis of iodixanol and mentions possible solvents in the same general way as in WO 99/18054, including alcohols.
It has now surprisingly been found that methanol can be used as solvent in the dimerisation step of Compound A in an industrial scale and will fulfill the requirements listed above.